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Aims: \ud Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.\ud \ud Methods and Results: \ud We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.\ud \ud Conclusion: \ud Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.\ud \ud Translational perspective: \ud New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

Background Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post‐ST‐segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery. Hypothesis: We hypothesized that segmental circumferential strain with displacement encoding with stimulated echoes (DENSE) would be a stronger predictor of infarct transmurality than feature‐tracking strain, and noninferior to extracellular volume fraction (ECV). Study Type: Prospective. Population: Fifty participants (mean ± SD, 59 ± 9 years, 40 [80%] male) underwent cardiac MRI on day 1 post‐STEMI. Field‐Strength/Sequences: 1.5T/cine, DENSE , T1 mapping, ECV , LGE. Assessment Two observers assessed segmental percentage LGE extent, presence of microvascular obstruction (MVO), circumferential and radial strain with DENSE and feature‐tracking, T1 relaxation times, and ECV. Statistical Tests: Normality was tested using the Shapiro–Wilk test. Skewed distributions were analyzed utilizing Mann–Whitney or Kruskal–Wallis tests and normal distributed data using independent t ‐tests. Diagnostic cutoff values were identified using the Youden index. The difference in area under the curve was compared using the z‐statistic. Results: Segmental circumferential strain with DENSE was associated with the extent of infarction ≥50% (AUC [95% CI], cutoff value = 0.9 [0.8, 0.9], −10%) similar to ECV (AUC = 0.8 [0.8, 0.9], 37%) (P = 0.117) and superior to feature‐tracking circumferential strain (AUC = 0.7[0.7, 0.8], −19%) (P

IntroductionThere is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75–0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia inGZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control.MethodsWe enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ).Results104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the targetGZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months.ConclusionsNon-invasive evidence of major ischaemia is uncommon in patients withGZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months.Trial registration numberNCT02425969.

Objectives The aim of this study was to test the hypothesis that invasive coronary function testing at time of angiography could help stratify management of angina patients without obstructive coronary artery disease. Background Medical therapy for angina guided by invasive coronary vascular function testing holds promise, but the longer-term effects on quality of life and clinical events are unknown among patients without obstructive disease. Methods A total of 151 patients with angina with symptoms and/or signs of ischemia and no obstructive coronary artery disease were randomized to stratified medical therapy guided by an interventional diagnostic procedure versus standard care (control group with blinded interventional diagnostic procedure results). The interventional diagnostic procedure–facilitated diagnosis (microvascular angina, vasospastic angina, both, or neither) was linked to guideline-based management. Pre-specified endpoints included 1-year patient-reported outcome measures (Seattle Angina Questionnaire, quality of life [EQ-5D]) and major adverse cardiac events (all-cause mortality, myocardial infarction, unstable angina hospitalization or revascularization, heart failure hospitalization, and cerebrovascular event) at subsequent follow-up. Results Between November 2016 and December 2017, 151 patients with ischemia and no obstructive coronary artery disease were randomized (n = 75 to the intervention group, n = 76 to the control group). At 1 year, overall angina (Seattle Angina Questionnaire summary score) improved in the intervention group by 27% (difference 13.6 units; 95% confidence interval: 7.3 to 19.9; p, Central Illustration

Aims A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. Methods and results After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR Conclusion Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

Objectives: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). Background: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with “surgical disease” instead underwent PCI. Methods: Between 1 March 2020 and 31 July 2020, 215 patients with recognized “surgical” CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. Results: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P =.008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P

Background: Patients with angina symptoms and/or signs of ischemia but no obstructive coronary artery disease (INOCA) pose a diagnostic and therapeutic challenge.Objectives: The purpose of ...

Background: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. Methods: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. Results: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17–55), the median LVEDP was 17 mm Hg (interquartile range, 12–21), and the correlation between them was not statistically significant ( r =0.15; P =0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P =0.045) and major adverse cardiac events (n=21 events; P =0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60–21.22] P =0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7–98.2; P =0.033) when LVEDP>18 was added to IMR>32. Conclusions: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02257294.

Background Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was Methods The primary outcome was compared between groups using a stratified Wilcoxon rank-sum test (van Elteren test), stratified by the location of the myocardial infarction. Results Among the 440 patients (mean age of 60.5 years; 15% women), the primary end point was measured in 396 (90%) patients, 17 (3.9%) withdrew, seven died and all other patients were followed up to 3 months. The amount (mean percentage of left ventricular mass) of microvascular obstruction was 2.3% versus 2.6% versus 3.5% in the placebo, 10 mg of alteplase and 20 mg of alteplase groups, respectively. In the primary analysis, microvascular obstruction did not differ between the 20 mg of alteplase group and the placebo group: 3.5% versus 2.3%, estimated difference 1.16% (95% confidence interval –0.08% to 2.41%; p = 0.32). In the secondary analysis, microvascular obstruction did not differ between the 10 mg of alteplase group and the placebo group: 2.6% versus 2.3%, estimated difference 0.29% (95% confidence interval –0.76% to 1.35%; p = 0.74). By 3 months, major adverse cardiac events (cardiac death, non-fatal myocardial infarction and unplanned hospitalisation for heart failure) had occurred in 15 (10.1%) patients in the placebo group, 18 (12.9%) in the 10 mg of alteplase group and 12 (8.2%) in the 20 mg of alteplase group. Conclusions Adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction compared with placebo. Limitations Premature discontinuation of enrolment limited the power of the secondary and safety analyses. Future work Low-dose intracoronary alteplase or tenecteplase could be compared with placebo at the end of primary percutaneous coronary intervention in patients with an ischaemic time of Trial registration This trial is registered as ClinicalTrials.gov NCT02257294. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 5. See the NIHR Journals Library website for further project information.

Supplemental Digital Content is available in the text., Background: The resistive reserve ratio (RRR) expresses the ratio between basal and hyperemic microvascular resistance. RRR measures the vasodilatory capacity of the microcirculation. We compared RRR, index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) for predicting microvascular obstruction (MVO), myocardial hemorrhage, infarct size, and clinical outcomes, after ST-segment–elevation myocardial infarction. Methods: In the T-TIME trial (Trial of Low-Dose Adjunctive Alteplase During Primary PCI), 440 patients with acute ST-segment–elevation myocardial infarction from 11 UK hospitals were prospectively enrolled. In a subset of 144 patients, IMR, CFR, and RRR were measured post-primary percutaneous coronary intervention. MVO extent (% left ventricular mass) was determined by cardiovascular magnetic resonance imaging at 2 to 7 days. Infarct size was determined at 3 months. One-year major adverse cardiac events, heart failure hospitalizations, and all-cause death/heart failure hospitalizations were assessed. Results: In these 144 patients (mean age, 59±11 years, 80% male), median IMR was 29.5 (interquartile range: 17.0–55.0), CFR was 1.4 (1.1–2.0), and RRR was 1.7 (1.3–2.3). MVO occurred in 41% of patients. IMR>40 was multivariably associated with more MVO (coefficient, 0.53 [95% CI, 0.05–1.02]; P=0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25–8.24]; P=0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84–9.26]; P=0.019), independently of CFR≤2.0, RRR≤1.7, myocardial perfusion grade≤1, and Thrombolysis in Myocardial Infarction frame count. RRR was multivariably associated with MVO extent (coefficient, −0.60 [95% CI, −0.97 to −0.23]; P=0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15–0.75]; P=0.008), and infarct size (coefficient, −3.41 [95% CI, −6.76 to −0.06]; P=0.046). IMR>40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80–15.81] P=0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70–11.70] P=0.002), and all-cause death/heart failure hospitalization (OR, 4.08 [95% CI, 1.55–10.79] P=0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19–0.99] P=0.047). CFR was not associated with infarct characteristics or clinical outcomes. Conclusions: In acute ST-segment–elevationl infarction, IMR and RRR, but not CFR, were associated with MVO, myocardial hemorrhage, infarct size, and clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02257294.

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST ‐segment–elevation myocardial infarction. In the T‐ TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T‐ TIME trial. From 2016 to 2017, patients with ST ‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (P =0.013), resistive reserve ratio ( P =0.026), and microvascular obstruction ( P =0.022), but not index of microcirculatory resistance. Conclusions In ST ‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02257294.

Supplemental Digital Content is available in the text., Background: Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA). Methods: Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3–3.0]; P=0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; P

Background Impaired microcirculatory reperfusion worsens prognosis post-primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Intracoronary (IC) alteplase targets persisting thrombus post-reperfusion & distal embolisation. In the T-TIME trial microvascular obstruction on cardiac magnetic resonance (CMR) did not differ with IC alteplase vs placebo. Purpose To prospectively determine if index of microcirculatory resistance (IMR) is lower & coronary flow reserve (CFR) or resistive reserve ratio (RRR) are higher (improved) with IC alteplase, & to provide mechanistic insights. Methods A pre-planned substudy of the main protocol. From 2016–2017, STEMI patients from 3 UK hospitals ≤6 hrs ischaemic time were randomised in a 1:1:1 dose-ranging, double-blind design. Following standard care reperfusion, alteplase (10 or 20mg) or placebo was infused over 5–10 mins proximal to the culprit lesion pre-stenting. IMR (primary outcome), CFR & RRR (secondary outcomes) were measured in the culprit artery post-PCI. Physiology results were obscured from clinicians acquiring the data, to maintain blinding. CMR was performed 2 days & 3 months post-STEMI. Subgroup analyses were prespecified including by ischaemic time (4 hrs) & IMR threshold >32. Results In 144 patients (mean age 59 yrs, 80% male), IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo (Table). Patients with ischaemic time 32, % ST-resolution at 60 mins was worse with alteplase 10mg vs placebo (23.1±53.9 vs 50.9±31.5) & in those with IMR≤32% ST-resolution at 60 mins was better with alteplase 20mg vs placebo (68.0±30.7 vs 39.1±43.2), p=0.002 for interaction. The CMR findings in the substudy & overall trial populations were consistent. Main results Placebo Alteplase 10mg Alteplase 20mg (n=53) (n=41) (n=50) IMR, median (IQR) 33.0 (17.0–57.0) 22.0 (17.0–42.0) 37.0 (20.0–57.8) p=0.15 p=0.78 CFR, median (IQR) 1.3 (1.1–1.8) 1.4 (1.1–1.9) 1.5 (1.1–2.0) p=0.92 p=0.74 RRR, median (IQR) 1.6 (1.3–2.2) 1.6 (1.4–2.6) 1.8 (1.3–2.4) p=0.69 p=0.81 P-values for comparison of alteplase with placebo. Conclusions In acute STEMI with ischaemic time ≤6 hrs, IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo. In those with shorter ischaemic times ( Acknowledgement/Funding Dr Maznyczka is funded by a fellowship from the British Heart Foundation (FS/16/74/32573). T-TIME was funded by grant 12/170/4 from NIHR-EME

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years’ follow-up (median [interquartile range], 744 [570–853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01895751.

Background Ischemia and no obstructive epicardial coronary artery disease (INOCA) is a common clinical syndrome with distinct underlying causes. Objective To evaluate the prevalence and predictors of microvascular and/or vasospastic angina (MVA/VSA) in an unselected cohort of angina patients referred for invasive coronary angiography with suspected ischaemic heart disease in whom obstructive coronary artery disease (CAD) is excluded. Methods Prospective cohort study at two regional centres between November 2016 and December 2017 including patients with symptoms and/or signs of ischaemia prior to undergoing invasive coronary angiography (NCT03193294). Baseline risk was assessed (ASSIGN score) and validated questionnaires were completed prior to the angiogram including Rose angina, quality of life (EuroQOL [EQ-5D-5L]) and angina severity according to the Seattle Angina Questionnaire (SAQ). Patients with definite or probable angina without CAD [diameter stenosis 0.80] proceeded directly to assessment for disorders of coronary vasomotion. This involved an ad hoc interventional diagnostic procedure (IDP) using reference invasive tests for microvascular angina (MVA), vasospastic angina (VSA), both conditions or none. MVA and VSA groups were compared before logistic regression was performed to assess predictors of MVA and VSA. Results Three hundred and ninety-one patients with angina were recruited before undergoing invasive coronary angiography during the study period. Overall, 185 (47%) of subjects had INOCA and 151 of these underwent an IDP. INOCA patients reported similar angina burden with worse quality of life than CAD subjects (EQ5D-5L index 0.60 v 0.65 units; P=0.041). The mean age of patients who underwent the IDP was 60.9 years, 74% were female and their median predicted 10-year IHD risk was 18.6% (10.6, 31.4). 78 subjects (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both (MVA & VSA) only 17 (11%) had non-cardiac chest pain. Myocardial bridging of coronary artery was found in 22 (15%). Multivariate predictors of MVA included typical angina, inducible ischaemia but traditional cardiovascular risk factors were not associated. Smoking and age were independent predictors of VSA. Conclusion The majority of patients with symptoms and/or signs of ischemia and no obstructive disease have a diagnosis of microvascular and/or vasospastic angina. Traditional cardiovascular risk scores have limited discrimination for disorders of coronary vasomotion. Conflict of Interest Nil

Aims Despite advances in understanding the physiological role of collaterals in coronary chronic total occlusions (CTOs), collateral anatomy remains poorly defined. Our aim was to define the anatomy and interventional utility of collaterals within a large population of patients with CTOs. Methods and results We studied the coronary angiograms of 481 patients with 519 CTOs at six centres in the U.K. over four years. Detailed angiographic analysis was performed by interventional cardiologists specialising in CTO percutaneous coronary intervention (PCI). All visible collaterals with a collateral connection (CC) grade ≥1 were recorded. A subgroup of CTOs (n=277) was assessed for interventional capability, defined as whether the collateral supply was able to facilitate retrograde access. We described 45 different collateral patterns: 20 in right coronary artery (RCA), 13 in left anterior descending (LAD), and 12 in circumflex artery CTOs. Septal collaterals from the LAD to the right posterior descending artery (RPDA), and from the posterior descending artery to the LAD were most common, and most often considered as having "interventional capability". Conclusions This is the largest analysis of collateral circulation anatomy in a population of patients with CTOs. We anticipate that these data will be of significant benefit in angiographic analysis and procedure planning for CTO PCI.

Background Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent ischaemia in a tissue remote from the heart. Its mechanisms are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium-dependent mechanism. Methods We performed a prospective, randomised, sham-controlled, blinded clinical trial. Patients with stable coronary artery disease undergoing elective angiography were randomised 1:1 to RIPC or sham. Endothelial-dependent and –independent function was assessed with intracoronary (ic) acetylcholine (ACh) and ic nitrate, respectively. Coronary luminal diameter was assessed by QCA. Primary outcome: between-group difference in mean% change in coronary luminal diameter following ACh. Results Following angiography, 60/75 patients (mean ±SD age 57.5±8.5 years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean% change in coronary luminal diameter was −13.3±22.3% and −2.0±17.2% in the sham and RIPC groups respectively (difference 11.32%, 95% CI: 1.2 to 21.4, p=0.032) (figure 1). This remained significant with age and sex as covariates (difference 11.01%, 1.01–21.0, p=0.035). Conclusions RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion, and this endothelium-dependent mechanism may contribute to its cardioprotective effects.

Answers 1. ECG No 1 (Figure 1) shows a broad complex irregularly irregular rythum which is consistent with atrial f ibrillation. The ventricular rate is very rapid and there is slow upstroke of R wave in the chest leads indicative of pre-excitation 2. DC Cardioversion is a safe option. In this patient DC Cardioversion was chosen due to the worrying rapid ventricular rate and risk of degeneration into ventricular f ibrillation (VF). Amiodrone in this situation can act as an atrio-ventricular (AV) node blocking agent and lead to unopposed AV conduction and risk of VF. 3. ECG No 2 (Figure 2) shows classical features of pre-excitation with short PR interval and delta wave in leads V2-V6; this is suggestive of the Wolff Parkinson White (WPW) syndrome. 4. Radiofrequency ablation of the accessory pathway is the treatment of choice Picture Quiz Answer: A young man with palpitations

Introduction Myocardial infarction and coronary artery disease in people under 40 years of age are relatively uncommon. To establish a diagnosis, physicians need a high degree of clinical suspicion. Case presentation We report the case of a 33-year-old Caucasian man presenting with classical signs and symptoms of acute pulmonary embolism. Subsequent investigations interestingly revealed right ventricular mural thrombus with no obvious underlying pathology triggering it. On cardiac magnetic resonance imaging, he was found to have a right ventricular infarct with secondary thrombus formation. Coronary angiography confirmed ostial occlusion of the right coronary artery. Conclusion This is an unusual case of premature myocardial infarction presenting primarily with secondary complications.